A tissue adhesive means a tissue adhesive to close biological tissues (henceforth referred to as tissues), such as blood vessels and skin, in an operation of cardiovascular surgery, etc. With use of this adhesive, it is possible to prevent blood leaking and such risks so as to improve the safety of the operation.
Tissue adhesives include the following three types. The first tissue adhesive is a cyanoacrylate based tissue adhesive, commercial products of which include DERMABOND. This type of tissue adhesive has a problem in that the biocompatibility is low, whereas the bonding strength is high. The second tissue adhesive is a biopolymer-aldehyde based tissue adhesive, commercial products of which include GRF glue. This type of tissue adhesive also has a problem in that the biocompatibility is low, whereas the bonding strength is high. The third tissue adhesive is a fibrin based tissue adhesive, commercial products of which include Bolheal. Conversely, this type of tissue adhesive has a problem in that the bonding strength is low, whereas the biocompatibility is high.
In recent years, it has been elucidated that a tissue adhesive including human serum albumin (henceforth referred to as HSA) and a crosslinking agent has high bonding strength (Non Patent Literature 1).
HSA is a serum protein made from blood and it is a globular protein having a molecular weight of 69,000 and a diameter of about 10 nm. This is a negatively charged acidic protein. In addition, disuccinimidyl tartarate (henceforth referred to as DST) has been used as the crosslinking agent.
However, since any product using a blood is classified into a medicinal product, considerable efforts are required for the approval and clearance. Moreover, once it is approved as a medicinal product, the usage record has to be kept continually for 20 years after the approval. This problematically requires considerable efforts.
For this reason, it has been considered to use gelatin, which is a non-blood preparation, instead of HSA. For example, Patent Literature 1 has disclosed a medical material prepared by crosslinking gelatin with succinimidized poly-L-glutamic acid. Moreover, Patent Literature 2 relates to a tissue adhesive film and has disclosed a tissue adhesive film made from gelatin or collagen. However, they have a problem in that the bonding strength is not enough.
In addition, Patent Literature 3 relating to a tissue adhesive formulation has disclosed a tissue adhesive formulation which includes a mixture of a synthetic and/or cross-linkable material in a particulate form and a particulate material. However, this tissue adhesive formulation also has a problem in that the bonding strength is not enough.
Moreover, there are papers relating to gelatin in which an alkyl group has been introduced on a side chain thereof (Non Patent Literatures 2 and 3). Furthermore, there is a paper including gelatin in which a cholesteryl group has been introduced on a side chain thereof and a tartaric acid crosslinking agent (Non Patent Literature 4).
Use of a hydrophobically modified gelatin in which a hydrophobic group has been introduced into a gelatin having a molecular weight of not less than 10000 and less than 50000 instead of HSA may make it possible to provide a tissue adhesive having high bonding strength and high biocompatibility.
Bonding properties can be improved if the molecular weight of gelatin is increased. However, there is an instance that, when a porcine-derived gelatin was used, the tissue adhesive did not turn to a liquid state and was hardened into a gel state even if the molecular weight of the gelatin was adjusted to about 20000, and so it failed in uniformly being applied to a bonding part when used as a tissue adhesive, and it was difficult to handle in terms of spreadability. In addition, there is an instance of jelling when it was left at rest at normal temperatures.
Moreover, addition of water-insoluble molecules, such as tartaric acid, to a water solvent made it impossible to uniformly disperse these molecules in the water solvent. A tissue adhesive in which such molecules are not dispersed uniformly caused varied bonding properties such as bonding strength and bonding stability.
Meanwhile, since a tissue adhesive composed of polyethylene glycol di-succinimidyl succinate (PEG-(SS)2), which is a water-soluble crosslinking agent, and HSA, has been approved in the U.S.A. under the product name ProGEL, it is highly probable that PEG-based polymers can be used well as a constituent of a tissue adhesive.